Therapeutic perspectives for adult soft tissue sarcoma—updates from the 2022 ASCO annual meeting

At the recent 2022 American Society of Clinical Oncology (ASCO) annual meeting, the latest progress was presented in clinical trials of various therapeutic modalities for adult soft tissue sarcoma (STS), including chemotherapy, targeted therapy, anti-immune checkpoint immunotherapy, and multiple combination treatments (Table 1) . Generally, the development of clinical treatments for STS is relatively slow, owing to the complex pathological subtypes of sarcoma and their heterogeneous biological behaviors. Here, we briefly summarize updates from this year’s ASCO meeting and discuss the future therapeutic perspectives for unspecific STS.

At the recent 2022 American Society of Clinical Oncology (ASCO) annual meeting, the latest progress was presented in clinical trials of various therapeutic modalities for adult soft tissue sarcoma (STS), including chemotherapy, targeted therapy, anti-immune checkpoint immunotherapy, and multiple combination treatments (Table 1). Generally, the development of clinical treatments for STS is relatively slow, owing to the complex pathological subtypes of sarcoma and their heterogeneous biological behaviors. Here, we briefly summarize updates from this year's ASCO meeting and discuss the future therapeutic perspectives for unspecific STS.

Chemotherapy
Through a variety of clinical trials and explorative research, traditional cytotoxic chemotherapy with anthracyclines (mainly doxorubicin or epirubicin) and ifosfamide (AI) remains the first-line regimen for most of adults with STS, regardless of histopathology type. Other drugs, including gemcitabine, docetaxel, dacarbazine, trabectedin, and eribulin, are selected as secondary or post-line setting treatments.
The STS 1001 neoadjuvant study, conducted by Italian, Spanish, French, and Polish sarcoma research groups, and published in 2020, has indicated that 3 pre-operative cycles of AI chemotherapy resulted in better survival outcomes than histotype-tailored settings in 5 major high-graded sarcoma subtypes. However, in the high-grade myxoid liposarcoma (MLPS) subgroup, neoadjuvant trabectedin had similar disease-free survival (DFS, HR 1.03) and overall survival (OS, HR 1.05) to those of an AI regimen 1 . In this year's meeting, an update was provided on an expansion study of high-grade MLPS with a non-inferiority design. With a median follow-up of 66 months, AI and trabectedin had comparable DFS (86% vs. 73%, P = 0.26) and OS (88% vs. 90%, P = 0.90) outcomes 2 . Meanwhile, trabectedin showed a better safety profile with much less hematological toxicity and slightly increased liver toxicity, which was primarily grade 1 or 2 2 . Moreover, neoadjuvant chemotherapy conferred an OS benefit for patients with MLPS, compared with the survival threshold predicted by the nomogram in the validated Sarculator tool 3 .
Beyond trabectedin, other new biological compounds including anti-microtubule agents such as eribulin and unesbulin, have been reported to treat certain STS subtypes, mainly leiomyosarcoma (LMS) and liposarcoma (LPS) 4,5 . A phase II study of trabectedin on retroperitoneal LPS and LMS, and a phase Ib study introducing a new microtubular inhibitor, unesbulin, combined with dacarbazine for LMS, were also presented at this year's ASCO meeting, thus suggesting promising anti-tumor roles of these treatments 6,7 .
In 2022 ASCO meeting, Zhou et al., at Zhongshan Hospital, Fudan University, China, reported the efficacy of eribulin

Targeted therapy
Multi-target small molecular tyrosine kinase inhibitors (TKI; mainly targeting VEGFR, FGFR, KIT, etc.) have been developed and approved for refractory STS in multiple regions worldwide; examples include pazopanib, regorafenib, and anlotinib. However, in 2 clinical trials presented this year, regorafenib and surufatinib both showed a very short PFS of approximately 2 months 9,10 . The specific anti-VEGFR2 TKI drug apatinib also showed encouraging efficacy in post-line treatment for metastatic STS. In our previous report on apatinib in treatment of metastatic STS after failure of chemotherapy, the best ORR, evaluated at 12 weeks, was 26.32% (10/38), and an mPFS of 7.87 m was achieved 11 . In combination treatments with chemotherapy, an update was provided on a phase Ib/II study of lenvatinib and eribulin in advanced LPS and LMS by researchers from Taiwan, China. The combination therapy achieved a 20% ORR and a median PFS of 8.6 months 12 . Interestingly, patients who received this therapy as first-line treatment appeared to achieve no further benefit, but had poorer response rates and disease control rates, thus suggesting that this treatment cannot yet challenge front-line treatment with AI and targeted therapy 12 .
Recently, progress has been made in advancing other directions in targeted therapy. Beyond previously reported epigenetic drugs such as EZH2 inhibitors and HDAC inhibitors, novel agents targeting genes in the MDM2-TP53 pathway and DNA damage repair pathway emerged in this year's ASCO meeting. BI907828, a highly potent oral MDM2-p53 antagonist, has been investigated in a phase I study in solid tumors, including advanced or metastatic LPS 13 . This modality has shown promising efficacy in both de-differentiated and well-differentiated LPS, with an ORR of 12.5% and 26.7%, respectively, and a DCR of 87.5% and 100%, respectively 13

Anti-immune checkpoint immunotherapy
Responses to immune checkpoint blockade therapies vary widely among heterogeneous subgroups of STS. Generally, sarcoma is treated as an immune "cold" tumor, because its cold tumor microenvironment usually does not respond to immunotherapy. However, previous studies have demonstrated that a high density of B cells and the presence of tertiary lymphoid structures (TLS) in tumors might be associated with better response rates to immunotherapy 16 . In the PEMBROSARC study, after recruitment of patients with TLS detected by immunohistochemistry on baseline tumor samples, the ORR for anti-PD1 monotherapy (pembrolizumab) increased to 30%, and the PFS was extended to 4.1 months 17 .
Updates on survival and a biomarker study of neoadjuvant nivolumab monotherapy or combination therapy with ipilimumab on resectable retroperitoneal LPS and extremity/truncal UPS were presented at this year's ASCO meeting. Patients with UPS received radiotherapy before the surgery. Intratumoral B-cell infiltration, TLS formation, and increased diversity and clonality of the intratumoral BCR repertoire at baseline were favorable prognostic factors for immunotherapy 18 . However, in contrast to the minimal pathologic response in the retroperitoneal LPS group receiving only immunotherapy, nearly 90% pathological hyalinization was observed in the UPS group after immunotherapy and radiation, thus suggesting that radiologic therapy might contribute to pathologic response in neoadjuvant immunotherapy treatments for UPS. The long term benefits of this neoadjuvant immunotherapeutic treatments remain to be confirmed in randomized controlled trials.
Efforts have been made to enhance immunotherapy by combing chemotherapy for STS in the past few years. Evidence of a synergistic interaction between these treatment types remains lacking. Survival updates for phase 2 trials using nivolumab, ipilimumab, and Trabectedin for previously untreated advanced STS were reported in this year's ASCO meeting, with an ORR of 26.6% 19 . Another combination of PD-1 inhibitor retifanlimab with chemotherapy with gemcitabine and docetaxel as first-line therapy in a phase I/II study was associated with a maximum ORR of 50% and a DCR of 100% 20 . However, the median PFS associated with both combinations above did not show a significant improvement and was limited to only 4-6 months.
A combination of VEGFR-TKI and anti-PD1 immunotherapy as a second-line treatment has also been widely explored in clinical trials as well as in real-world practice. We previously reported a retrospective study on biomarker investigation and the efficacy of anti-PD1 immunotherapy in Chinese patients with bone and soft tissue sarcoma after failure of traditional chemotherapy treatment; most patients (20/24) received camrelizumab (anti-PD1) combined with apatinib (VEGFR2-TKI) 21 . The ORR and DCR were 16.7% and 55.6%, respectively, and the PFS reached 7.59 months 21 . In translational studies of this patient cohort, we have found that conventional biomarkers, including TMB, TNB, MSI, HLA-LOH, and PD-L1 expression, and sarcoma types are not associated with clinical response. However, higher intratumoral heterogeneity, a higher percentage of immune cell infiltration, and lower stromal gene expression is detected in responders than non-responders 21 .

Cellular therapy
Cellular therapy, particularly T cell receptor-engineered T cell (TCR-T) treatment, has made outstanding progress for adult STS, as reported in this year's ASCO meeting. Two types of NY-ESO-1-specific TCT-T therapy developed in the US and China in HLA-A*02 patients, were introduced for advanced STS. Letetresgene atuoleucel (lete-cel; GSK3377794) had previously achieved a maximum ORR of 50% and a PFS of 14.5 months in synovial sarcoma (SS). In a pilot study on myxoid/ round cell liposarcoma (MRCLS) presented this year, the ORR also reached 40%, with a PFS of 8.7 months in patients receiving standard high-dose lymphodepletion 22 . Comparatively, Chinese TAEST16001 cells, another TCR affinity enhanced specific-T-cell therapy, achieved an ORR of 41.7% and a PFS of 7.2 months in the STS group mostly comprising the SS histotype 23 . Updated data on the SPEARHEAD-1 trial of afamitresgene antoleucel (Afami-cel) in SS and MRCLS expressing MAGE-A4 indicated an ORR of 36.2% in all patients and 40.7% in the SS cohort, and a median PFS exceeding 1 year in responders 24 .
The new horizon of cellular immunotherapy has come into view for a variety of cancers. However, several issues faced in real-world clinical practice might limit the expansion and the development of cellular therapy. Among them, prolonged cytopenia due to lymphodepletion chemotherapy before T-cell infusion is a critical concern. Furthermore, previous trials have indicated that different lymphodepletion conditions might affect treatment efficacy 25 . Recently, new CAR-T cells designed with synthetic chimeric receptors with an orthogonal IL-2r extracellular domain fused with an IL-9r intracellular domain have been described, which can also be expanded in the absence of conditioning lymphodepletion 25 . This technology may support the development of more efficient, safer cellular therapies in the future.

Future perspectives
Future perspectives in the medical treatment of soft tissue sarcomas include several dimensions. Generally, therapeutic approaches will develop in both a sarcoma subtype dependent and a sarcoma subtype agnostic manner.
For most sarcoma types, traditional cytotoxic chemotherapy, mainly with an AI regimen, remains the standard frontline treatment for advanced adult STS. Novel agents such as Trabectedin and eribulin might be applied as post-line treatments for certain histotypes. Moreover, combination treatments with these novel and conventional cytotoxic agents, or the combination of chemotherapy with other treatments including immunotherapy, anti-angiogenetic agents such as endostatin, antibodies to VEGF(R), or TKI should be further investigated in front-line settings 26 . Recently another phase III randomized trial, the LMS-04 trial, has demonstrated that doxorubicin plus trabectedin in first-line therapy, compared with doxorubicin alone, significantly increases PFS in patients with LMS 27 .
For tumor-type dependent therapy, next generation sequencing and molecular tumor board based targeted therapies should help achieve more precision treatments for STS patients. Targeting driver mutations such as BRAF, ALK, NTRK, ROS1, EZH1/2, and KIT in certain rare types of sarcomas has been reported to be associated with relatively high response rates. A recent study has validated RET as a tissue-agnostic target with sensitivity to RET inhibition by pralsetinib, with an ORR as high as 57% in RET fusion-positive solid tumors, including several subtypes of sarcoma 28 . In other sarcomas, a lack of confirmed driven mutations, or genomic aberrations in some other oncogenic regulation pathways, can be exploited for therapeutic approaches, such the D-cyclin-CDK4/6-INK4a-Rb pathway, MDM2-TP53 pathway, and BRACness in the homologous recombination DNA repair pathway. Moreover, novel compounds targeting non-mutational epigenetic alterations, such as inhibitors of IDH1, ATR, DNMT, HDACs, and BET, have also been investigated in early-phase trials in patients with sarcoma 29 .
In immunotherapy, most sarcoma subtypes, except for certain sensitive subtypes, such as alveolar soft part sarcoma, UPS, myxoid fibrosarcoma, and angiosarcoma, have low tumor immunogenicity and respond poorly to immune checkpoint blockade. In-depth investigation of the tumor associated microenvironment, particularly the immune microenvironment, has identified an "immune-high" subgroup of sarcomas characterized by elevated expression of a B cell-associated gene signature, CD8+T cell infiltration, and intratumoral TLSs 16 . Screening patients with these effective biomarkers and combining other treatments to target the tumor microenvironment, are key to improving the clinical response to immunotherapy. Moreover, individualized cellular therapy including TCR-T and CAR-T therapy might be the most effective treatment for patients with advanced and refractory disease.
Nevertheless, in real-world clinical practice, comprehensive considerations by multidisciplinary teams and molecular tumor boards (MTB) are urgently required to formulate a precise therapeutic strategy for each patient with advanced and refractory STS, particularly for patients with high-grade, multiply recurrent, or large tumors adhering to important vessels or nerves. Pre-operative treatment including systemic medication, radiation, or interventional therapy should be considered to ensure radical resection, to decrease the recurrence rate, and to improve overall outcomes. Therefore, trials of neoadjuvant therapies should be encouraged in sarcomas, to investigate the efficacy and safety of new compounds or combination treatments in relatively short periods. Moreover, biomarker explorations could be conducted through analysis of both preand pro-treatment tumor or liquid samples.